Animal models of anorexia and cachexia

Abstract

BACKGROUND: Cachexia is a devastating syndrome of body wasting that worsens quality of life and survival for patients suffering from diseases such as cancer, chronic kidney disease and chronic heart failure. Successful treatments have been elusive in humans, leaving a clear need for the development of new treatment compounds. Animal models of cachexia are able to recapitulate the clinical findings from human disease and have provided a much-needed means of testing the efficacy of prospective therapies. OBJECTIVE: This review focuses on animal models of cachexia caused by cancer, chronic heart failure and chronic kidney disease, including the features of these models, their implementation, and commonly-followed outcome measures. CONCLUSION: Given a dire clinical need for effective treatments of cachexia, animal models will continue a vital role in assessing the efficacy and safety of potential treatments prior to testing in humans. Also important in the future will be the use of animal models to assess the durability of effect from anti-cachexia treatments and their effect on prognosis of the underlying disease states.

Figure 1

Tumor implantation to produce cancer cachexia. Tumor cells from tissue culture are initially implanted in a donor mouse/rat prior and grown up prior to dividing between compound- and vehicle-treated animals. This approach better insures equal division of tumor cells between treatment groups.

Figure 2

Changes in food intake and body weight in tumor-bearing animals. A. Mice implanted with Lewis Lung Carcinoma exhibited gradual decrease in food intake starting 4 days after tumor implantation. This decrease in food intake was ameliorated in a dose-dependant manner during 4 days of treatment with a melanocortin antagonist. (Used by permission from reference [23].) B. Mice implanted with C26 adenocarcinoma exhibited weight loss starting 12 days after tumor implantion. This weight loss was blocked via oral treatment with a melanocortin antagonist starting the day after tumor implantation. (Reproduced from Weyermann P et al. Orally available selective melanocortin-4 receptor antagonists stimulate food intake and reduce cancer-induced cachexia in mice. PLoS One 2009;4:e4774, with permission [26].)

Figure 3

Location of suture placement to ligate the left anterior descending artery. In the LAD ligation model, a sternotomy reveals the anterior surface of the heart, though the artery itself can be variable and is not visible to the surgeon. A suture is placed just inferior to the left atrium to block all perfusion distal to that point (Figure adapted from Green EL, editor: Biology of the Laboratory Mouse. ed Second, Ben Harbor, Maine, The Jackson Laboratory, 1968 [85] with permission.)

Figure 4

Surgical approach and weight effects of the 5/6 nephrectomy model. A. During the first stage of the procedure, one kidney is isolated and the upper and lower portion are excised and cauterized to leave the central 1/3 of the kidney functional. A second procedure then removes the contralateral kidney approximately 1 week later. (Photo by author.) B. Following the second procedure, weight gain is compromised vs. sham-treated animals but may be improved, as shown here during treatment with ghrelin. (Figure adapted from DeBoer MD et al. Ghrelin treatment of chronic kidney disease: improvements in lean body mass and cytokine profile. Endocrinology 2008;149:827–835. [44]; with permission.